The objective of the Program is to study the molecular regulation of the outgrowth, patterning, and regeneration of the developing vertebrate limb. In Project 1, the hypothesis that the extracellular macromolecule hyaluronan (HA) facilitates the outgrowth, proliferation, and directed migration of limb mesenchymal cells in response to the apical ectodermal ridge (AER) will be investigated, as will the hypothesis that HA acts in concert with the EGFR/ErbB signaling network in the regulation of limb outgrowth and patterning. The role of HA in regulating the onset of limb cartilage differentiation will also be studied, as will its role in AER activity. In Project 2, the roles of the EGFR/ErbB family of tyrosine kinase receptors and ligands in the formation and function of the AER and in the signaling pathways that control limb patterning along the anteroposterior and dorsoventral axes will be investigated, as will role of EGFR/ErbB signaling in the programmed cell death involved in shaping limb contours. In Project 3, the cellular and molecular mechanisms that regulate digit tip regeneration in the embryonic mouse limb bud and the AER-dependent regeneration of the chick limb bud will be studied. In particular, the roles of directed cell migration and differential cell adhesion in the regeneration response will be investigated, as will the roles and relationships among Dlx genes, Msx genes, BMP signaling, FGFs, EGFR/ErbB signaling, and hyaluronan in the control of mammalian digit tip and chick limb bud regeneration. The Projects will be supported by an Administrative Core (Core A) that will manage the financial aspects of the research budgets.